The basis of autoimmune thyroid disease remains unclear. Most investigations into the pathogenesis of these disorders have focused on immune abnormalities that might lead to an autoimmune response. However, no unique genetic basis has been identified for the immune response to thyroid autoantigens, and many individuals who demonstrate autoimmune responses to thyroid antigens do not develop autoimmune disease. Apoptosis, the process most likely responsible for thyroid cell death in thyroiditis, is closely regulated. Work from our laboratory indicates that apoptosis is specifically regulated in thyroid follicular cells in several unique ways, and that the induction of immune-mediated apoptosis can be blocked or facilitated in a manner that could alter the induction of cytotoxicity. These finding have led to the hypothesis that the regulation of programmed cell death pathways in the thyroid has a significant role in the development of thyroiditis. Altered apoptosis could contribute to the pathogenesis of thyroiditis either by facilitating initial cellular damage that leads to an immune response or by accelerating immune-mediated apoptosis of thyrocytes that results in hypothyroidism. This proposal seeks to examine this hypothesis with four specific aims. The first specific aim will document the expression and function of proteins that are involved in specific cell-death pathways in thyroid follicular cells. These molecules include receptors and ligands involved in at least four distinct cell death signaling pathways. The second specific aim will examine the regulation of the apoptotic pathways present in thyroid cells, particularly the signaling pathways that potentially mediate immune damage to thyroid cells. The third specific aim involves an examination of regulation of the common apoptotic pathway in thyroid follicular cells, which mediates cell death through CASPASE activation, mitochondrial damage and cleavage of death substrates. The expression and regulation of molecules, such as members of the Bcl-2 family, that modulate this process will be clarified and the role that Vitamin D, estrogen, other steroid hormones, and iodine-induced oxidative stress play in modifying the apoptotic potential of thyroid cells will also be addressed. The fourth specific aim will confirm that the identified alterations in apoptosis can alter the susceptibility of thyroid cells to immune mediated cell death in vivo, first by an examination in thyroid slices and by analyzing the expression of death pathway molecules in thyroid cells derived from normal glands vs. thyroiditis. Animal studies involving treatment with specific hormones that alter apoptosis in the thyroid or transgenic animals will also confirm that alterations in death pathways can change the physiology of normal thyroid cells or alter the pathophysiology of thyroiditis. These studies will help to clarify how thyroid cells can be damaged by autoimmune responses and could provide insights into the physiologic regulation of thyroid cell turnover.